Br Heart Jf 1986;56:483-5

Crescentic glomerulonephritis: a possiblecomplication of streptokinase treatment formyocardial infarctionNEIL MURRAY,* JOHN LYONS,* MARGARET CHAPPELLt

From the *London Chest Hospital and tRoyal Free Hospital, London

SUMMARY Twenty days after a streptokinase infusion given for myocardial infarction, a patientdeveloped a group G streptococcal throat infection. Thirteen days later he presented with a serumsickness type illness and progressive renal failure. Renal biopsy showed crescentic glomerulo-nephritis.

Case report

A 56 year old man was admitted with a two hour Am,history of retrosternal pain. The electrocardiogram .demonstrated 2 mm ST segment elevation in the ianterior leads suggestive of acute myocardial ;infarction. As part of a clinical trial he received anintravenous infusion of 1-8 million units of strepto-kinase (Kabikinase, Kabivitrum) over 60 minutes, ; @,-after premedication with 100 mg of hydrocortisone.During the infusion ventricular fibrillation devel- . - 3 :oped. This reverted to sinus rhythm with a single ' !k ;;>DC shock. There were no prolonged periods ofhypotension. The electrocardiogram progressed to W12show T wave inversion but Q waves did not evolve. -.Creatine kinase concentration rose to a maximum of w267 U/l (normal < 200 U/1) and the asparate trans- ;taminase to 66 U/I (normal < 40 U/l) on day 2 (strep-tokinase infusion given on day 0). During his stay in , C'ihospital he was treated with lignocaine, frusemide,amiloride, and metoprolol. He was mobilised anddischarged on day 9.Twenty days after the streptokinase infusion a _

sore throat developed and on day 33 he was re-admitted with swelling of the hands and feet andbilateral calf pain. He had a purpuric rash over thelower abdomen and legs and multiple splinter hae- fimorrhages. There was no evidence of heart failure. # ^ -jProteinuria and microscopic haematuria werepresent and urine microscopy showed hyaline casts.On admission plasma urea was 6-9 mmol/l, cre- Fig 1 Photomicrograph showing crescenticatinine 115 jsmol/l, sodium 136 mmol/l, and potas- glomerulonephritis. The section was stained with periodic

acid Mallory Schiff reagent. The asterisk indicates cellularcrescents; large arrow, atrophied tubules; small arrow,

Requests for reprints to Dr Neil Murray, Department of Cardi- damaged tubular epithelium; arrowhead, collapsed

ology, Groby Road Hospital, Groby Road, Leicester LE3 9QE. glomerular tuft.483

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484sium 5-1 mmol/l. An autoantibody screen was nega-tive. The antistreptolysin 0 titre was > 1000(normal < 100) and ( haemolytic streptococciLancefield Group G were cultured from a throatswab. Hypersensitivity to the streptococcal antigenwas diagnosed. By day 44 plasma urea had risen to19-1 mmol/l and creatinine to 464 jmol/l. Oral pred-nisolone, 30 mg daily, and fluid restriction werestarted. Renal function continued to deteriorate andthe plasma urea rose to 57 mmol/l. He became oli-guric and peritoneal dialysis was started on day 49.A renal biopsy was performed on day 61, 28 days

after development of leg pains and purpura. All glo-meruli in the biopsy showed large cellular crescentswith an underlying segmental proliferative glomeru-lonephritis (fig 1). Capillary thrombi were present ina few loops and there was widespread necrosis andinfiltration by polymorphonuclear leucocytes. Noarteritis was seen. Tubular damage was severe, overa quarter of tubules being atrophied with inter-stitial fibrosis. There was moderate oedema and a

Fig 2 Electronmicrograph showing crescenticglomerulonephritis. Ep, epithelial cell with fusedfootprocesses. En, swollen endothelial cell. The arrow indicatessubendothelial electron dense deposits.

Murray, Lyons, Chappellpatchy interstitial inflammatory infiltrate. Electronmicroscopy showed segmentally distributed sub-endothelial and mesangial electron dense depositswith fusion of the epithelial foot processes (fig 2).

Cyclophosphamide (100 mg daily) was given inaddition to prednisolone. He continued to requireintermittent peritoneal dialysis for three weeks.After this dialysis was stopped and the plasma ureaconcentration remained steady at 20 mmol/l with anadequate urine output. He developed effort relatedchest pain which was eased by sublingual nitrates.In view of his renal failure, coronary angiographywas not performed, and he was treated with a (3blocker. He was discharged on day 105 when theplasma urea concentration was 18 mmol/l. Two dayslater he had a prolonged episode of chest pain andwas readmitted with electrocardiographic evidenceof a new anterior myocardial infarction. Furtherthrombolytic treatment was not given. On this oc-casion Q waves did evolve on the electrocardiogramand the creatine kinase concentration rose to 2661U/1. He was mobilised without further pain. At dis-charge he was well. Plasma urea concentration was19 mmol/l. Subsequently his renal function againdeteriorated and he required further dialysis. A sec-ond renal biopsy specimen showed similar changesto the first but many crescents were now fibrousand there was more extensive tubular atrophy andinterstitial fibrosis. Tissue was obtained forimmunofluorescence studies and these showed seg-mentally distributed IgM, C3, and Clq.

Discussion

The development of crescentic glomerulonephritisas part of a serum sickness type illness after theadministration of streptokinase and a subsequentstreptococcal infection suggests a causal link with atleast one of these antecedents. This patient hadreceived other drugs, none of which have beenreported as being associated with renal failure.Streptokinase, however, is antigenic, and bron-chospasm, angioneurotic oedema, and anaphylaxishave been associated with its administration.1 2Hypersensitivity to streptococcal antigens is also oneof the commonest causes of proliferative glomeru-lonephritis.3

Renal failure has been reported after streptokinaseand has been attributed to various aetiologies. Cho-lesterol embolisation of the renal circulation hasbeen suggested and confirmed at necropsy.4sThrombolysis is thought to remove a protective coat

of thrombus overlying an ulcerated atheromatousplaque, allowing widespread diffuse embolisation ofthe underlying cholesterol crystals. Interstitialnephritis6 as well as "serum sickness" due to

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Crescentric glomerulonephritis after streptokinase treatment 485immune complexes have also been suggested onclinical grounds but have not been proven by histo.rlogical examination.

In this case the renal failure was shown to becaused by crescentic glomerulonephritis with anunderlying segmental proliferative glomerulo-nephritis that apparently was the result of immunecomplex deposition. There are several possiblepathogenic mechanisms to consider. First, this mayhave been an acute serum sickness type III hyper-sensitivity reaction to streptokinase. This has beenpostulated elsewhere7 and is supported by theaccompanying purpura. In experimental serum sick-ness the lesions are evidently due to immune com-plexes and appear during the immune phase of anti-gen elimination, usually about 10 to 14 days afterexposure to antigen. Typically the lesions are mostsevere at 13 days and heal rapidly, so that within twoor three weeks- the glomeruli appear normal.8-0 Inmost animals with these lesions antigen and immunecomplex concentrations have dropped almost to zeroby 15 days. In the previously reported case, in whichhistological examination was not available, clinicalmanifestations appeared seven days after the start ofstreptokinase treatment.7 In our case the lesions didnot appear until day 33. This delay is longer thanwould be expected, although probably not imposs-ibly so.

Secondly, the glomerulonephritis may have beena straightforward post-streptococcal phenomenon.The delay between the sore throat and the appear-ance of typical lesions is usually 1-4 weeks. " This isconsistent with the 13 day delay seen in this case.While post-streptococcal glomerulonephritis is typi-cally endocapillary in nature, a small proportion areof the crescentic type as demonstrated here." Simi-larly, while purpuric rashes and splinter hae-morrhages are uncommon, they do sometimesoccur. On the other hand, the aetiological agent inpost-streptococcal glomerulonephritis is almostinvariably a group A rather than group G strep-tococcus. Furthermore, in this patient the typicalsubepithelial humps could not be identified on elec-tron microscopy.A third possibility is that the illness was due to a

type III hypersensitivity reaction to the group Gstreptococcus after sensitisation by streptokinase.The evidence for this is circumstantial and the sug-gestion is speculative. This possibility should be

considered, however, because neither of the othertwo possibilities fully explain this case.

In this patient the renal failure may have beena simple post-streptococcal phenomenon andexposure to streptokinase may have been irrelevant.If, however, the glomerulonephritis was the result ofsome form of streptokinase hypersensitivity this is aserious complication of streptokinase treatment.New thrombolytic agents, such as tissue plas-minogen activator, may not cause such allergic reac-tions. Experience with this agent is limited, how-ever, and its possible antigenicity is as yetunknown. 1 2

We thank Dr R Winwood for permission to report apatient under his care.

References

1 Bell WR, Meek AG. Guidelines for the use of throm-bolytic agents. N Engl J Med 1979;301:1266-70.

2 Baumgartner TG, Glen Davis R. Streptokinase-induced anaphylactic reaction. Clin Pharmacol1982;1:470-1.

3 Heptinstall RH. Pathology of the kidney. 3rd ed. Bostonand Toronto: Little, Brown, 1983:387.

4 Rieben FW, Waldherr R, Oster P, Schettler G. AkutesNierenversagen als Folge diffuser Cholesterin-kristall-Embolisation unter Streptokinasetherapie.Dtsch Med Wochenschr 1979;104:1447-9.

5 Andrassy K. Discussion. p194. In: Ritz E, Bommer J,Andrassy K, Waldherr R. Acute renal failure, hyper-tension and skin necrosis in a patient with strepto-kinase therapy. Am J Nephrol 1984;4:193-200.

6 Pick RA, Joswig BC, Cheung AK, Cohen IM. Acuterenal failure following repeated streptokinase therapyfor pulmonary embolism. West J Med 1983;138:878-80.

7 Totty WG, Romano T, Benian GM, Gilula LA,Sherman LA. Serum sickness following strepto-kinase therapy. AJR 1982;138:143-4.

8 Heptinstall RH. Pathology of the kidney. 3rd ed. Bostonand Toronto: Little, Brown, 1983:301-9.

9 Germuth FG. Comparative histologic and immuno-logic study in rabbits of induced hypersensitivity ofserum sickness type. J Exp Med 1953;97:257-82.

10 Wilson CB, Dixon FJ. Antigen quantitation in experi-mental immune complex glomerulonephritis. I Acuteserum sickness. J Immunol 1970;105:279-90.

11 Heptinstall RH. Pathology of the kidney. 3rd ed. Bostonand Toronto: Little, Brown, 1983:395-401.

12 Sherry S. Tissue plasminogen activator (t-PA). Will itfulfil its promise? N Engl J Med 1985;313:1014-7.

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